OBJECTIVES: Due to limited research on the association between recurrence of mood episodes and the longitudinal course of neurocognitive functioning in early phase bipolar I disorder (BD I), the impact of recurrence on neurocognition remains unclear. Further, a strong correlation between neurocognitive impairment and functional impairment has been demonstrated. The longitudinal relationship between neurocognitive impairment and functional outcome in relation to recurrence is, however, not established. METHODS: The current study investigated the longitudinal relationship between neurocognition, recurrence of mood episodes and functional outcome in a sample of first-treatment (FT) BD I patients (N = 42), with and without relapse, during a 1-year follow-up period. The longitudinal course of neurocognitive functioning in the patients was also compared to that of a group of healthy controls (N = 143). RESULTS: Compared to both patients with relapse and healthy controls, no-relapse patients showed neurocognitive improvements. The polarity of the relapse episodes was mostly depressive, and for the no-relapse patients, reduction of symptoms was associated with neurocognitive improvement. No-relapse patients showed better global and occupational functioning. CONCLUSIONS: The current study found different neurocognitive and functional trajectories in FT BD I patients with and without relapse, with differences at follow-up to some degree being mediated by current symptoms. The current findings highlight the importance of treatment focusing on neurocognition and symptom states with the aim of improving functional recovery.

Background A potential link between increase in total cholesterol and triglycerides and clinical improvement has been observed during antipsychotic drug treatment in chronic schizophrenia patients, possibly due to drug related effects on lipid biosynthesis. We examined whether changes in serum lipids are associated with alleviation of psychosis symptoms after one year of antipsychotic drug treatment in a cohort of first-episode psychosis (FEP) patients. Methods A total of 132 non-affective antipsychotic-treated FEP patients were included through the Norwegian Thematically Organized Psychosis (TOP) project. Data on antipsychotic usage, serum lipids (total cholesterol, high-density lipoprotein (HDL) cholesterol, low-density lipoprotein (LDL) cholesterol and triglycerides (TG)), body mass index (BMI) and clinical state were obtained at baseline and after 12 months. The Positive and Negative Syndrome Scale (PANSS) was used to assess psychotic symptoms. Mixed-effects models were employed to examine the relationship between serum lipids and psychotic symptoms while controlling for potential confounders including BMI. Results An increase in HDL during one year of antipsychotic treatment was associated with reduction in PANSS negative subscores (B = − 0.48, p = 0.03). This relationship was not affected by concurrent change in BMI (adjusted HDL: B = − 0.54, p = 0.02). No significant associations were found between serum lipids, BMI and PANSS positive subscores. Conclusion We found that an increase in HDL level during antipsychotic treatment is associated with improvement in negative symptoms in FEP. These findings warrant further investigation to clarify the interaction between lipid pathways and psychosis.

As findings on the neuropathological and behavioral components of Alzheimer’s disease (AD) continue to accrue, converging evidence suggests that macroscale brain functional disruptions may mediate their association. Recent developments on theoretical neuroscience indicate that instantaneous patterns of brain connectivity and metastability may be a key mechanism in neural communication underlying cognitive performance. However, the potential significance of these patterns across the AD spectrum remains virtually unexplored. We assessed the clinical sensitivity of static and dynamic functional brain disruptions across the AD spectrum using resting-state fMRI in a sample consisting of AD patients (n = 80) and subjects with either mild (n = 44) or subjective (n = 26) cognitive impairment (MCI, SCI). Spatial maps constituting the nodes in the functional brain network and their associated time-series were estimated using spatial group independent component analysis and dual regression, and whole-brain oscillatory activity was analyzed both globally (metastability) and locally (static and dynamic connectivity). Instantaneous phase metrics showed functional coupling alterations in AD compared to MCI and SCI, both static (putamen, dorsal and default-mode) and dynamic (temporal, frontal-superior and default-mode), along with decreased global metastability. The results suggest that brains of AD patients display altered oscillatory patterns, in agreement with theoretical premises on cognitive dynamics.

A meta-analysis of publicly available summary statistics on multiple sclerosis combined with three Nordic multiple sclerosis cohorts (21,079 cases, 371,198 controls) revealed seven sequence variants associating with multiple sclerosis, not reported previously. Using polygenic risk scores based on public summary statistics of variants outside the major histocompatibility complex region we quantified genetic overlap between common autoimmune diseases in Icelanders and identified disease clusters characterized by autoantibody presence/absence. As multiple sclerosis-polygenic risk scores captures the risk of primary biliary cirrhosis and vice versa (P = 1.6 x 10(-7), 4.3 x 10(-9)) we used primary biliary cirrhosis as a proxy-phenotype for multiple sclerosis, the idea being that variants conferring risk of primary biliary cirrhosis have a prior probability of conferring risk of multiple sclerosis. We tested 255 variants forming the primary biliary cirrhosis-polygenic risk score and found seven multiple sclerosis-associating variants not correlated with any previously established multiple sclerosis variants. Most of the variants discovered are close to or within immune-related genes. One is a low-frequency missense variant in TYK2, another is a missense variant in MTHFR that reduces the function of the encoded enzyme affecting methionine metabolism, reported to be dysregulated in multiple sclerosis brain.

Background Several lines of evidence show that the immune system is implicated in the pathophysiology of major depressive disorder (MDD) and that treatment with antidepressants affects cytokine and C-reactive protein (CRP) levels. Few studies have investigated immune markers during non-pharmacological treatment. In this follow-up study, we investigated whether CRP and elevated plasma cytokine levels observed before treatment of an acute episode of MDD are normalized during non-pharmacological treatment. Methods We obtained clinical assessments and blood for CRP and cytokine analysis from 50 unmedicated MDD patients, and cytokine levels from healthy controls. The patients received ‘therapy as usual’ for 12 weeks, and the assessments were then repeated. Of the 43 completers, 29 patients did not receive medication. Results In the patients receiving treatment without antidepressants, the depressive symptoms and the plasma levels of eight cytokines (interleukin (IL)-1Ra, IL-5,-6,-8,-10, G-CSF, IFN-γ, and TNF-α) were significantly reduced (P = 0.002–0.048). The cytokine levels were no longer different from the controls. The plasma CRP level did not change. Conclusion Cytokine plasma levels normalized during recovery from an acute depressive episode in MDD without antidepressant treatment. These findings may have implications for the understanding of the role of the immune system in depression and recovery from depression.

Background. First-episode psychosis (FEP) patients show structural brain abnormalities. Whether the changes are progressive or not remain under debate, and the results from longitudinal magnetic resonance imaging (MRI) studies are mixed. We investigated if FEP patients showed a different pattern of regional brain structural change over a 1-year period compared with healthy controls, and if putative changes correlated with clinical characteristics and outcome. Method. MRIs of 79 FEP patients [SCID-I-verified diagnoses: schizophrenia, psychotic bipolar disorder, or other psychoses, mean age 27.6 (S.D. = 7.7) years, 66% male] and 82 healthy controls [age 29.3 (S.D. = 7.2) years, 66% male] were acquired from the same 1.5 T scanner at baseline and 1-year follow-up as part of the Thematically Organized Psychosis (TOP) study, Oslo, Norway. Scans were automatically processed with the longitudinal stream in FreeSurfer that creates an unbiased within-subject template image. General linear models were used to analyse longitudinal change in a wide range of subcortical volumes and detailed thickness and surface area estimates across the entire cortex, and associations with clinical characteristics. Results. FEP patients and controls did not differ significantly in annual percentage change in cortical thickness or area in any cortical region, or in any of the subcortical structures after adjustment for multiple comparisons. Within the FEP group, duration of untreated psychosis, age at illness onset, antipsychotic medication use and remission at follow-up were not related to longitudinal brain change. Conclusions. We found no significant longitudinal brain changes over a 1-year period in FEP patients. Our results do not support early progressive brain changes in psychotic disorders.

Objective: This study compared cortical and sub-cortical volumes between patients with complicated (i.e. presence of intracranial abnormality on the day-of-injury CT) and uncomplicated (i.e. absence of intracranial abnormality) mild traumatic brain injury (MTBI) 4 weeks post-injury. The study hypothesized regionally decreased brain volumes and reduced cortical thickness in patients with complicated MTBIs compared with uncomplicated MTBI. Methods: This study was part of a larger 2 years cohort study on MTBI. Baseline clinical and magnetic resonance imaging (MRI) data were compared for those with complicated and uncomplicated MTBI. It identified 168 patients with MTBI (90 uncomplicated and 78 complicated), aged 16–65 years. 3T MRI-system (Signa HDxt, GE Medical Systems, Milwaukee, WI) and cortical reconstruction and volumetric segmentation by FreeSurfer software have been used. Results: No significant differences between uncomplicated and complicated MTBIs were found in neuroanatomic volumes and cortical thickness after controlling for age, gender and education. The complicated MTBI group showed larger ventricles compared with the uncomplicated group, but this effect diluted when adjusting for potential confounders. Conclusion: The study findings suggest that the classification of complicated and uncomplicated MTBI may be too broad to differentiate volumetric and morphometric effects of injury in the early post-injury phase.

Considerable uncertainty exists about the defining brain changes associated with bipolar disorder (BD). Understanding and quantifying the sources of uncertainty can help generate novel clinical hypotheses about etiology and assist in the development of biomarkers for indexing disease progression and prognosis. Here we were interested in quantifying case–control differences in intracranial volume (ICV) and each of eight subcortical brain measures: nucleus accumbens, amygdala, caudate, hippocampus, globus pallidus, putamen, thalamus, lateral ventricles. In a large study of 1710 BD patients and 2594 healthy controls, we found consistent volumetric reductions in BD patients for mean hippocampus (Cohen’s d=−0.232; P=3.50 × 10−7) and thalamus (d=−0.148; P=4.27 × 10−3) and enlarged lateral ventricles (d=−0.260; P=3.93 × 10−5) in patients. No significant effect of age at illness onset was detected. Stratifying patients based on clinical subtype (BD type I or type II) revealed that BDI patients had significantly larger lateral ventricles and smaller hippocampus and amygdala than controls. However, when comparing BDI and BDII patients directly, we did not detect any significant differences in brain volume. This likely represents similar etiology between BD subtype classifications. Exploratory analyses revealed significantly larger thalamic volumes in patients taking lithium compared with patients not taking lithium. We detected no significant differences between BDII patients and controls in the largest such comparison to date. Findings in this study should be interpreted with caution and with careful consideration of the limitations inherent to meta-analyzed neuroimaging comparisons.

BACKGROUND: Recent genome-wide association studies have identified a large number of genetic risk factors for schizophrenia (SCZ) featuring ion channels and calcium transporters. For some of these risk factors, independent prior investigations have examined the effects of genetic alterations on the cellular electrical excitability and calcium homeostasis. In the present proof-of-concept study, we harnessed these experimental results for modeling of computational properties on layer V cortical pyramidal cells and identified possible common alterations in behavior across SCZ-related genes. METHODS: We applied a biophysically detailed multicompartmental model to study the excitability of a layer V pyramidal cell. We reviewed the literature on functional genomics for variants of genes associated with SCZ and used changes in neuron model parameters to represent the effects of these variants. RESULTS: We present and apply a framework for examining the effects of subtle single nucleotide polymorphisms in ion channel and calcium transporter-encoding genes on neuron excitability. Our analysis indicates that most of the considered SCZ-related genetic variants affect the spiking behavior and intracellular calcium dynamics resulting from summation of inputs across the dendritic tree. CONCLUSIONS: Our results suggest that alteration in the ability of a single neuron to integrate the inputs and scale its excitability may constitute a fundamental mechanistic contributor to mental disease, alongside the previously proposed deficits in synaptic communication and network behavior. Keywords: Biophysical modeling, Functional genomics, Genome-wide association studies, Layer V pyramidal cell, Neuron excitability, Schizophrenia

BACKGROUND: There are indications that low S-25(OH)D is associated with increased disease severity in psychotic disorder. Our first aim was to investigate the relations between low S-25(OH)D and positive, negative and depressive symptoms. Our second aim was to explore if associations between S-25(OH)D and symptoms were influenced by levels of inflammatory markers. METHODS: Participants (N=358) with a medical history of one or more psychotic episodes were recruited. Current symptomatology was assessed by The Structured Interview for the Positive and Negative Syndrome Scaleanalyzed by a five-factor model. The Calgary Depression Scale for Schizophrenia was used to assess depression and suicidal ideation. Blood samples were analyzed for S-25(OH)D, CRP, sTNF-R1, IL-Ra and OPG. We performed bivariate correlations and multiple regression models to evaluate the effect of S-25(OH)D on the outcomes. RESULTS: Low S-25(OH)D was significantly associated with negative symptoms (adjusted R2=0.113, F(6,357)=8.58, p<0.001) and with depression (adjusted R2=0.045, F(4,357)=5.233, p<0.001) when adjusting for possible confounding factors (i.e. gender, education, diagnose, hospitalization status, ethnicity, season and thyroid status). CRP was correlated with both S-25(OH)D (rho=-0.13, p=0.02) and negative symptoms (rho=0.14, p=0.01), but did not act as a mediator. The correlations between S-25(OH)D and the inflammatory markers sTNF-R1, IL-Ra and OPG were not significant. CONCLUSION: There is a strong association between low S-25(OH)D and higher negative and depressive symptoms in psychotic disorders. Randomized controlled trials should be performed to investigate the effect of vitamin D supplementation as adjuvant treatment strategy in patients with prominent negative or depressive symptoms.

Lowered plasma tryptophan (TRP) and TRP/competing amino acid (CAA) ratio may be involved in the pathophysiology of major depression (MDD). Increased cortisol and immune-inflammatory mediators in MDD may affect the availability of TRP to the brain. We investigated whether baseline or post-treatment TRP, CAAs and TRP/CAA ratio are associated with a treatment response in MDD and whether these effects may be mediated by cortisol or immune biomarkers. We included 50 medication-free MDD patients with a depressive episode (DSM diagnosis) and assessed symptom severity with the Inventory of Depressive Symptomatology (IDS) before and after treatment as usual for 12 weeks (endpoint). Plasma levels of TRP, CAAs, the ratio, cortisol, CRP and 6 selected cytokines were assayed. The primary outcome was a 50% reduction in the IDS, while the secondary was a remission of the depressive episode. In IDS non-responders, CAAs increased and the TRP/CAA ratio decreased, while in IDS responders CAAs decreased and the TRP/CAA ratio increased from baseline to endpoint. In patients who were still depressed at endpoint TRP and CAAs levels had increased from baseline, while in remitted patients no such effects were found. Increases in CAAs were inversely correlated with changes in interleukin-1 receptor antagonist levels. The results show that increased CAA levels from baseline to endpoint are associated with a non-response to treatment in MDD patients. This suggests that the mechanism underpinning the CAA-related treatment resistance may be related to changes in immune pathways. CAA levels and amino acid metabolism may be new drug targets in depression.

Cannabis use disorder is associated with an earlier age at onset and a more severe outcome of schizophrenia spectrum disorders. The role of cannabis use before the onset of illness (premorbid cannabis use) has not been fully investigated. We here examined how amount and type of premorbid cannabis use was associated with the later course of illness including current substance use, symptoms and level of functioning in schizophrenia spectrum disorder. We used a naturalistic sample of patients with DSM-IV schizophrenia spectrum disorders with a comprehensive history of illness and substance use. Data on premorbid substance use was obtained from comprehensive self-report. The relationship to outcome was investigated using regression models that included current substance use and premorbid functioning. Pre-schizophrenia cannabis use was significantly associated with more severe psychotic symptoms and impaired functioning. Higher levels of premorbid cannabis use were associated with higher levels of current psychotic symptoms. These associations were independent of current substance use and premorbid functioning. Early use of cannabis (age <17 years) was associated with earlier age at onset of psychosis, independently of potential confounders. Pre-psychosis cannabis use affects illness outcome in schizophrenia spectrum disorders, and is associated with lower age at onset of psychosis. These findings of independent negative effects of premorbid cannabis use in schizophrenia suggest that a limitation of the general use of cannabis may have beneficial health effects.

In line with the notion of a continuously active and dynamic brain, functional networks identified during rest correspond with those revealed by task-fMRI. Characterizing the dynamic cross-talk between these network nodes is key to understanding the successful implementation of effortful cognitive processing in healthy individuals and its breakdown in a variety of conditions involving aberrant brain biology and cognitive dysfunction. We employed advanced network modeling on fMRI data collected during a task involving sustained attentive tracking of objects at two load levels and during rest. Using multivariate techniques, we demonstrate that attentional load levels can be significantly discriminated, and from a resting-state condition, the accuracy approaches 100%, by means of estimates of between-node functional connectivity. Several network edges were modulated during task engagement: The dorsal attention network increased connectivity with a visual node, while decreasing connectivity with motor and sensory nodes. Also, we observed a decoupling between left and right hemisphere dorsal visual streams. These results support the notion of dynamic network reconfigurations based on attentional effort. No simple correspondence between node signal amplitude change and node connectivity modulations was found, thus network modeling provides novel information beyond what is revealed by conventional task-fMRI analysis. The current decoding of attentional states confirms that edge connectivity contains highly predictive information about the mental state of the individual, and the approach shows promise for the utilization in clinical contexts.

Aim: Lack of insight into illness is frequent in psychotic disorders and seen as part of their primary pathology. The recognition of symptoms as psychotic, and beliefs about treatment alternatives, is also influenced by socio-cultural factors. Here we examined clinical insight into illness and beliefs about psychosis in immigrants in their first episode of psychosis compared to a reference group. Methods: 277 first episode psychosis participants were recruited to this cross-sectional study; 40 first- and 40 second-generation immigrants from Europe, Americas and Oceania (n=37), Asia including Turkey (n=28), or Africa (n=15). The Birchwood Insight Scale was used to measure clinical insight and “The Attitudes and Beliefs about Mental Health Problems”, schizophrenia version to assess socio-cultural beliefs. Results: Immigrants did not differ from the reference sample in clinical insight. After controlling for education level first generation immigrants were less likely to recognize psychotic symptoms (OR 2.9; Wald = 8.977, df 1, p =.003) and viewed hospitalization (OR 5.2; Wald = 20.388, df 1, p =.001) and treatment by a psychiatrist (OR 4.9; Wald = 6.609, df 1, p =.01)) as less beneficial than the reference group. Immigrants from Asia held more alternative explanations (OR 0.3; Wald = 6.567, df 1, p=.010). There were significantly stronger associations between clinical insight and socio-cultural beliefs in the reference group. Conclusions: Socio-cultural beliefs about psychosis in immigrants in first episode psychosis calls for more tailored information to this group, and emphasize the importance of treatment interventions involving both a cultural and personal perspective of insight.

The atypical antipsychotic drug aripiprazole is a partial dopamine (DA) D2 receptor agonist, which differentiates it from most other antipsychotics. This study compares the brain activation characteristic produced by aripiprazole with that of haloperidol, a typical D2 receptor antagonist. Healthy participants received an acute oral dose of haloperidol, aripiprazole or placebo, and then performed an active aversive conditioning task with aversive and neutral events presented as sounds, while blood-oxygen-level-dependent (BOLD) functional magnetic resonance imaging (fMRI) was carried out. The fMRI task, targeting the mesolimbic motivational system that is thought to be disturbed in psychosis, was based on the conditioned avoidance response (CAR) animal model – a widely used test of therapeutic potential of antipsychotic drugs. In line with the CAR animal model, the present results show that subjects given haloperidol were not able to avoid more aversive than neutral task trials, even though the response times were shorter during aversive events. In the aripiprazole and placebo groups more aversive than neutral events were avoided. Accordingly, the task-related BOLD-fMRI response in the mesolimbic motivational system was diminished in the haloperidol group compared to the placebo group, particularly in the ventral striatum, whereas the aripiprazole group showed task-related activations intermediate of the placebo and haloperidol groups. The current results show differential effects on brain function by aripiprazole and haloperidol, probably related to altered DA transmission. This supports the use of pharmacological fMRI to study antipsychotic properties in humans

Aim To investigate self-reported psychiatric and somatic symptoms and health service use at age 16 in persons who later developed a psychotic disorder compared with a control group from the same geographical areas. Method Responses concerning psychiatric or somatic health and health service use from Norwegian youth studies in a cohort of 15- and 16-year-olds in three Norwegian counties (N = 11 101, 90% response rate) were gathered. The questionnaire responses from persons later identified with a lifetime diagnosis of DSM-IV (Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition) psychotic disorders (n = 30) (confirmed psychosis, CP) were compared with responses from the rest of the group (population control, PC) (n = 11 067). Follow-up analyses were made for cases with a confirmed onset of a psychotic disorder after the time of the survey (n = 21). Results The main significant differences between the CP and PC groups were more self-reported anxiety, depression and ‘feeling in need of treatment for eating disorders’ at age 16 in the CP group. The rate of self-reported eating disorder symptoms alone reached the level of statistical significance in the follow-up analyses. The CP group did not use available health services to a markedly greater extent than the control group. Conclusion We found that, in comparison with others, youths who were later identified with a psychotic disorder reported more symptoms at age 16.

Background It has been suggested that the development of depressive symptoms as a result of cytokine therapy is attributable to cytokine-induced elevated activity of the kynurenine pathway. The few studies of this mechanism in patients with common major depressive disorder (MDD) have yielded inconsistent results. The aim of the present study was to identify markers of the kynurenine pathway in a clinical MDD sample with increased cytokine levels. Methods Fifty medication-free MDD patients with a depressive episode and 34 healthy controls were included at baseline; the patients were followed for 12 weeks. Before initiating treatment, the patients were diagnosed and assessed for depressive symptoms and their blood was analyzed for tryptophan and its metabolites in the kynurenine pathway. The clinical assessments and metabolite measurements were repeated after 12 weeks of “treatment as usual”. Results We did not find significant elevation of kynurenine plasma markers in patients with a depressive episode compared to healthy controls, despite elevated cytokine levels in the patients. Clinical depression scores were significantly reduced after 12 weeks, but no significant change in the plasma kynurenine pathway plasma markers was observed. Conclusion The obtained results do not support the hypothesis that MDD depressive episodes are associated with elevated activity in the kynurenine pathway. This suggests that the pathophysiology underlying depressive episodes in common MDD differs from that of interferon induced depression. Our results warrant further study of the interplay between the kynurenine pathway and the cytokine activation patterns in these conditions.

The standard analysis approach in neuroimaging genetics studies is the mass-univariate linear modeling (MULM) approach. From a statistical view, however, this approach is disadvantageous, as it is computationally intensive, cannot account for complex multivariate relationships, and has to be corrected for multiple testing. In contrast, multivariate methods offer the opportunity to include combined information from multiple variants to discover meaningful associations between genetic and brain imaging data. We assessed three multivariate techniques, partial least squares correlation (PLSC), sparse canonical correlation analysis (sparse CCA) and Bayesian inter-battery factor analysis (Bayesian IBFA), with respect to their ability to detect multivariate genotype-phenotype associations. Our goal was to systematically compare these three approaches with respect to their performance and to assess their suitability for high-dimensional and multi-collinearly dependent data as is the case in neuroimaging genetics studies. In a series of simulations using both linearly independent and multi-collinear data, we show that sparse CCA and PLSC are suitable even for very high-dimensional collinear imaging data sets. Among those two, the predictive power was higher for sparse CCA when voxel numbers were below 400 times sample size and candidate SNPs were considered. Accordingly, we recommend Sparse CCA for candidate phenotype, candidate SNP studies. When voxel numbers exceeded 500 times sample size, the predictive power was the highest for PLSC. Therefore, PLSC can be considered a promising technique for multivariate modeling of high-dimensional brain-SNP-associations. In contrast, Bayesian IBFA cannot be recommended, since additional post-processing steps were necessary to detect causal relations. To verify the applicability of sparse CCA and PLSC, we applied them to an experimental imaging genetics data set provided for us. Most importantly, application of both methods replicated the findings of this data set.

Sleep is a universal phenomenon necessary for maintaining homeostasis and function across a range of organs. Lack of sleep has severe health-related consequences affecting whole-body functioning, yet no other organ is as severely affected as the brain. The neurophysiological mechanisms underlying these deficits are poorly understood. Here, we characterize the dynamic changes in brain connectivity profiles inflicted by sleep deprivation and how they deviate from regular daily variability. To this end, we obtained functional magnetic resonance imaging data from 60 young, adult male participants, scanned in the morning and evening of the same day and again the following morning. 41 participants underwent total sleep deprivation before the third scan, whereas the remainder had another night of regular sleep. Sleep deprivation strongly altered the connectivity of several resting-state networks, including dorsal attention, default mode, and hippocampal networks. Multivariate classification based on connectivity profiles predicted deprivation state with high accuracy, corroborating the robustness of the findings on an individual level. Finally, correlation analysis suggested that morning-to-evening connectivity changes were reverted by sleep (control group)-a pattern which did not occur after deprivation. We conclude that both, a day of waking and a night of sleep deprivation dynamically alter the brain functional connectome.

Schizophrenia is a highly heritable and polygenic disease, and identified common genetic variants have shown weak individual effects. Many studies have reported altered working memory (WM)-related brain activation in schizophrenia, preferentially in the frontal lobe. Such differences in brain activations could reflect inherited alterations possibly involved in the disease etiology, or rather secondary disease-related mechanisms. The use of polygenic risk scores (PGRS) based on a large number of risk polymorphisms with small effects is a valuable approach to examine the effect of cumulative genetic risk on brain functioning. This study examined the impact of cumulative genetic risk for schizophrenia on WM-related brain activations, assessed with functional magnetic resonance imaging. For each participant (63 schizophrenia patients and 118 healthy controls), we calculated a PGRS for schizophrenia based on 18 862 single-nucleotide polymorphism in a large multicenter genome-wide association study including 9146 schizophrenia patients and 12 111 controls, performed by the Psychiatric Genomics Consortium. As expected, the PGRS was significantly higher in patients compared with healthy controls. Further, the PGRS was related to differences in frontal lobe brain activation between high and low WM demand. Specifically, even in absence of main effects of diagnosis, increased PGRS was associated with decreased activation difference in the right middle-superior prefrontal cortex (BA 10/11) and the right inferior frontal gyrus (BA 45). This effect was seen in both cases and controls, and was not influenced by sex, age, or task performance. The findings support the notion of dysregulation of frontal lobe functioning as an inherited vulnerability factor in schizophrenia.

Vitamin D deficiency is common among patients with psychotic disorders and could be due to unknown disease mechanisms or contingent factors. However most studies are performed in chronic patients and have often failed to address the influence of ethnicity on vitamin D levels in clinical samples. We investigated serum concentrations of 25-hydroxy vitamin D (S-25 OH D) in first episode patients compared to patients with multi episodes and healthy controls; with a specific focus on differences between visible ethnic minorities and participants from the majority population. A total of 284 participants were included in this cross-sectional study. First episode patients with a DSM-IV psychotic disorder were matched on age, gender and ethnicity to participants from a multi episode patient sample (1:1) and healthy controls (1:2). We did not find any differences between either patient groups or the healthy controls, but participants from visible ethnic minorities had significantly lower S-25 OH D than participants from the majority population. This implies that S-25 OH D should be routinely measured in persons from visible ethnic minorities since low levels are associated with higher levels of depressive symptoms

We conducted a search for rare, functional variants altering susceptibility to Alzheimer’s disease that exploited knowledge of common variants associated with the same disease. We found that loss-of-function variants in ABCA7 confer risk of Alzheimer’s disease in Icelanders (odds ratio (OR) = 2. 2, P = 2.2× 10- 3) and discovered that the association replicated in study groups from Europe and the United States (combined OR = 2.03, P = 6.8×10-5).

The profile of brain structural abnormalities in schizophrenia is still not fully understood, despite decades of research using brain scans. To validate a prospective meta-analysis approach to analyzing multicenter neuroimaging data, we analyzed brain MRI scans from 2028 schizophrenia patients and 2540 healthy controls, assessed with standardized methods at 15 centers worldwide. We identified subcortical brain volumes that differentiated patients from controls, and ranked them according to their effect sizes. Compared with healthy controls, patients with schizophrenia had smaller hippocampus (Cohen’s d = − 0.46), amygdala (d = − 0.31), thalamus (d = − 0.31), accumbens (d = − 0.25) and intracranial volumes (d = − 0.12), as well as larger pallidum (d = 0.21) and lateral ventricle volumes (d = 0.37). Putamen and pallidum volume augmentations were positively associated with duration of illness and hippocampal deficits scaled with the proportion of unmedicated patients. Worldwide cooperative analyses of brain imaging data support a profile of subcortical abnormalities in schizophrenia, which is consistent with that based on traditional meta-analytic approaches. This first ENIGMA Schizophrenia Working Group study validates that collaborative data analyses can readily be used across brain phenotypes and disorders and encourages analysis and data sharing efforts to further our understanding of severe mental illness.

Etiologies of psychotic disorders (schizophrenia and bipolar disorder) are conceptualized as interplay between genetic and environmental factors. The adolescent period is characterized by changes in social roles and expectations that may interact with biological changes or psychosocial stressors. Few studies focus on the adolescents’ own reports of perceived risk factors. To assess differences at age 16 between persons who later develop psychotic disorders (“Confirmed Psychosis”, CP) and their class-mates (“Population Controls”, PC) we collected information on: (1) Social support factors (size of social network and expectancies of social support from friends), (2) Cognitive functioning (concentrating in the classroom, actual grades and expectancies of own academic achievements) and (3) Problems and stressors in families (illness or loss of work for parents), and in relationship with others (exposure to bullying, violence or sexual violation). Self-reported data from students at 15–16 years of age were linked to the case-registers from the “Thematically Organized Psychosis (TOP) Study”. The CP group reported more economic problems in their families, smaller social network and lower academic expectation than the PC group. The results support the notion that long-term socioeconomic stressors in adolescence may serve as risk factors for the development of psychotic disorders

Abstract Background: Cytokines are implicated in the pathophysiology of major depressive disorder (MDD). However, the pattern of alterations in cytokine levels is still unclear. The current study investigated the plasma levels of a range of cytokines in a follow-up design, with the aim of determining their involvement in depression. Methods: Fifty medication-free MDD patients with a depressive episode and 34 healthy controls were included at baseline; the patients were followed up after 12 weeks. Before initiating treatment, the patients were diagnosed and assessed for depressive symptoms and blood for cytokine analysis was obtained. The same clinical assessments and cytokine measurements were performed after 12 weeks of ‘‘treatment as usual.’’ Results: The cytokines interleukin (IL)-1b, IL-1 receptor antagonist (IL-1Ra), IL-5, IL-6, IL-7, IL-8, IL-10, granulocyte colony-stimulating factor (G-CSF), and interferon gamma (IFNg) were significantly elevated ( p = 0.01—0.047) in depressed patients at baseline compared to healthy controls.

Although several reviews show that cognitive behavioral therapy (CBT) is an effective treatment for patients with chronic psychosis, the effects of CBT on patients with a first-episode psychosis are less clear. Patients undergoing a first-episode psychosis are unique in that not only are they struggling with the symptoms of the disease, but also the realization of the diagnosis. Understanding how the disease will impact their lives with respect to changes in social goals, roles, and status can also lead to depression, anxiety and low self-esteem. The main aim of the present study is to describe two clinical cases in order to demonstrate the application of CBT in first-episode psychosis patients in an early stage of their psychosis. The two cases are individuals who were in an ongoing CBT trial for first-episode psychosis patients with symptoms of social anxiety, depression, and low self-esteem. Individual case formulations based on these symptoms were developed. Psychoeducation, normalizing, evaluation of negative automatic thoughts and dysfunctional schematic beliefs, and focusing on the negative consequences of safety behavior were the main treatment targets in attempting to improve the patients' symptoms and functioning. Both patients showed improvement in depressive symptoms, self-esteem, and general functioning. The cases described suggest that treatment designed to target depression, anxiety, and self-esteem in patients with first-episode psychosis could have potential beneficial effects; specific studies of this approach are recommended

AIM: The aim of the study was to explore if patients with migration and/or ethnic minority background have longer duration of untreated psychosis (DUP) than patients from the reference population, and in case to what extent this was best explained by ethnic minority status or migration background, including age at migration. METHODS: Four hundred sixty-two first-episode patients were included. The Structured Clinical Interview for Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition Axis I Disorders was used for diagnostic purposes. Patients were interviewed about migration history and ethnicity using structured questionnaires. RESULTS: Being part of an ethnic minority group had a trend-level significance, and migration after the age of 6 had a statistically significant association with prolonged DUP. CONCLUSIONS: Age at migration has a moderate, but statistically significant effect on DUP. The findings indicate migrating after school start is associated with a longer DUP in immigrant populations.